Tetraacetylribonamide and process of making it



Patented Jan. 6, 1 948 UNITED STATES PATENT cl rics TETRAACETYLRIBONAMIDE AND -P-ROGESS OF MAKING .IT

Max Tishl'er, Rahway, N. J assignor to Merck & 00., Inc., Rahway, N. J., a corporation of New Jersey No Drawing. Application July 26, 1945,

Serial No. 607,261

- according to this invention are represented by the general formula:

O=CNH2 HCOR noon

noon

HzC O R wherein R is an acyl group. In accordance with this invention, these novel compounds are prepared by reactions represented as follows, R again representing an acyl group:

O=CNH2 O=C]3NH2 noon HOOR I HO OH acylating H O R I agent 5 H0011 H OR H2C OH H2COR It is now discovered, according to this invention, that tetraacyl ribonami'de may be obtained by acyla-ting ribonamide; tetraacyl ribonicacid may be obtained by treating tetraacyl ribonamide with an oxide of nitrogen; and that a tetraacyl ribonyl halide may be obtained by treating a tetraacyl ribonic acid or salt thereof, with a halide or oxyhalide of phosphorus or sulfur.

The tetraacyl ribonyl halide compound may be reduced to tetraacyl ribose which may then be used in the synthesis of riboflavin.

The following examples illustrate methods of carrying out the present invention, but it is to be understood that these examples are given by way of illustration and not of limitation.

Example 1 Fifteen grams of ribonamide are added to a mixture of 74 cc. of acetic anhydride and 75 cc. of dry pyridine. The suspension is warmed with agitation until the solid dissolves. The solution is allowed to stand overnight at room tempera- The residue is washed with ether.

2 ture. The tetraacetyl ribonamide which crystallizes out of the reaction mixture is filteredoll'. Yield (first crop)-=14.7 g.; MJP. 124-5 C.

The filtrat is added with stirring to 200cc.'*of ice water and allowed to stand in an ice b'ath for one hour. A second crop is filtered off, and washed with water, followed by-% alcohol and ether. Yield (second crop) :63 g.; M. R1235- 124.5 C.

The filtrate from the second crop is extracted with 4x50 cc. of chloroform. The chloroform extract is washed with dilute (5%) sodium bicarbonate solution, then with water, the chloroform solution is then dried over Na2SO4, and

evaporated under reduced pressure to dryness. Yield (third crop) =3.'2.g.; M. P. 123--123.5 C. Total yieldi- 24.2 g. or 80% of theory.

Example 2 Twenty-six grams of cadmium ribonate (prepared from calcium d-arabonate by epimerization) are dissolved in cc. of water, by heating on a steam bath. While the mixture is being heated to 60-70 C., hydrogen sulfide is passed into the solution with stirring until a filtered test portion no longer reacts with hydrogen sulfide. The mixture is filtered and the cadmium sulfide washed with hot water. The washings and iii]- trates are combined and concentrated under reduced pressure to dryness. The residue is then heated-at 50-90 C. under reduced pressure for one hour. The syrupylactoneon standing slowly crystallizes but for subsequent operations, the syrup may be used without anypurification,

The syrupy ribonic acid lactone is dissolved in 150 cc. of absolute alcohol by warming. The solution is then cooled to 5 C., and while stirring, a solution containing two equivalents of ammonia and methyl alcohol is added dropwise. The mixture immediately becomes turbid and the product begins to separate very soon. As soon as the product begins to separate, the rate of ammonia addition may be greatly increased. The mixture is allowed to stand at between 0 and 5 C. for two hours after all the ammonia has been added, is then filtered, and the d-ribonamide obtained as a residue is washed with cold methyl alcohol. Yield, 16.5 to 17.5 g.. M. P. 138-139 C., with decomposition. An additional small crop of product may be obtained by concentrating the mother liquor under reduced pressure. Methyl alcohol may also be used as a solvent with no difference in yield.

A mixture of 10 g. of d-ribonamide, 38 cc. of

acetic anhydride and 50 cc. of dry pyridine is heated on a steam bath until solution occurs, and then for an additional 15 minutes. The solution is then allowed to stand for hour at room temperature. Ice is added together with seeds of the acetylated amide. After filtering ofi the crystalline material, the mother liquor is extracted with chloroform, washed, dried, and concentrated.

The residue is taken up in ether and diluted with petroleum ether whereby an additional yield of product separates. may be purified by recrystallization from methyl. alcohol and melts at 125-6 0. Yield 82%. 7 Alternatively, a mixtureof 200 g. of d-ribonamide, 175 g. of fused zinc chloride, and 1200 cc. of acetic anhydride-is stirred at C. for two hours. solves.

which becomes dark on standing, is poured into three liters of ice water, and, while stirring and maintaining the temperature below 25 C., a solution of 260 g. of sodium hydroxide in 500 cc. of water is added. The mixture is then filtered and the product recrystallized. An additional quantity of product may be obtained from the mother liquor by extracting with chloroform and proceeding as described above. Yield 227 g.

Example 3 Example 4 grams of ribonamide is added in'small portions over a period of one hour to a mixture'of 55 cc. of butyric anhydride and 10 cc. of pyridine which is stirred and maintained at 105 C. After all of the ribonamide has been added the mixture is kept between IOU-105 C. for an'additional halfhour. The solution is cooled and allowed to stand overnight at 0 C. Thecrystals whichseparateare filtered and washed with coldjabsolute alcohol. On recrystallization from absolute alcohol, the product, tetrabutyryl ribonamide, i obtained. (M. P. 935-94 0.) I

The tetraacetyl d-ribonamide During this time the ribonamide dis- The mixture is then placed in the cold room at about 3 C. for ten hours. The solution,

4 Example 5 A mixture of about 34 cc. of acetic anhydride and about 10 g. of pyridine is stirred and heated to approximately C. A .total of 10 g. of solid ribonamide is added in small portions Within one hour. Considerable heat is evolved in this reaction; therefore, the mixture is cooled from the outside and the reaction temperature of 60 is maintained by the rate of addition of ribonamide. The temperature has to be checked continuously since a temperature rise may occur rather suddenly. After all of the ribonamide has been added, the mixture is kept between 55 and 60 for half an hour. At this point the solution should be clear and colorless; it is cooled to 0 C. and kept there for 2 hours with stirring. The tetraacetyl ribonamide is then filtered and washed with absolute ethanol which has previously been cooled to 0 C. There should be no odor of pyridine or acetic anhydride in the first crop, The filtrate and the alcohol wash. are kept separately. The filtrate is concentrated as soon as possible and a second crop is, obtained by cooling the concentrate to 0 C. for 2 hours. This is filtered and washed like the first crop. If the volume of filtrate is considerable, it should be concentrated for a third crop. The combined alcohol washings are also concentrated and will yield a small amount of tetraacetyl ribonamide. The tetraacetyl ribonamide is air dried at 50. Yield=% theory. (M. P. 122-124 C.)

Other tetraacyl ribonamides can be obtained by reacting different aliphatic or aromatic acids, acid anhydrides, or acid halides, with ribonamide as above described. For example, tetrabenzoyl ribonamide may be obtained by reacting a benzoyl halide or benzoic anhydride with ribonamide.

Modifications may be made in carrying out the present invention without departing from the spirit and scope thereof, and the invention is to be limited only by the appended claims,

What is claimed is:

l. Tetraacetylribonamide.

2. The process that comprises reacting ribonamide with acetic anhydride in the presence of zinc chloride to produce tetraacetylribonamide.

MAX TISHLER.

REFERENCES CITED UNITED STATES PATENTS Name Date Pasternacket a1. Apr. 1, 1941 Number 

